Pairing MCL-1 inhibition with venetoclax improves therapeutic efficiency of BH3-mimetics in AML.
Antineoplastic Agents
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Bridged Bicyclo Compounds, Heterocyclic
/ administration & dosage
Cell Line, Tumor
Cells, Cultured
Coculture Techniques
Drug Resistance, Neoplasm
/ drug effects
Drug Synergism
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mesenchymal Stem Cells
/ drug effects
Myeloid Cell Leukemia Sequence 1 Protein
/ antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Pyrimidines
/ administration & dosage
Sulfonamides
/ administration & dosage
Thiophenes
/ administration & dosage
BCL-2
MCL-1
S63845
acute myeloid leukemia
venetoclax (ABT-199)
Journal
European journal of haematology
ISSN: 1600-0609
Titre abrégé: Eur J Haematol
Pays: England
ID NLM: 8703985
Informations de publication
Date de publication:
Nov 2020
Nov 2020
Historique:
received:
13
05
2020
revised:
01
07
2020
accepted:
09
07
2020
pubmed:
14
7
2020
medline:
30
7
2021
entrez:
14
7
2020
Statut:
ppublish
Résumé
Venetoclax combined with hypomethylating agents is a new therapeutic strategy frequently used for treating AML patients who are not eligible for conventional chemotherapy. However, high response rates are heterogeneous due to different mechanisms mediating resistance to venetoclax such as up-regulation of MCL-1 expression. We thus tested the anti-leukemic activity of S63845, a specific MCL-1 inhibitor. Apoptosis induces by S63845 with or without venetoclax was evaluated in primary AML samples and in AML cell lines co-cultured or not with bone marrow (BM) mesenchymal stromal cells. Sensitivity of leukemic cells to S63845 was correlated to the expression level of BCL-2, MCL-1, and BCL-XL determined by Western Blot and mass spectrometry-based proteomics. We observed that even if MCL-1 expression is weak compared to BCL-2, S63845 induces apoptosis of AML cells and strongly synergizes with venetoclax. Furthermore, AML cells resistant to venetoclax are highly sensitive to S63845. Interestingly, the synergistic effect of S63845 toward venetoclax-mediated apoptosis of AML cells is still observed in a context of interaction with the BM microenvironment that intrinsically mediates resistance to BCL2 inhibition. These results are therefore of great relevance for clinicians as they provide the rational for combining BCL-2 and MCL-1 inhibition in AML.
Substances chimiques
Antineoplastic Agents
0
BCL2 protein, human
0
Bridged Bicyclo Compounds, Heterocyclic
0
MCL1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Proto-Oncogene Proteins c-bcl-2
0
Pyrimidines
0
S63845
0
Sulfonamides
0
Thiophenes
0
venetoclax
N54AIC43PW
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
588-596Subventions
Organisme : Institut National Du Cancer
ID : ASC16044KSA
Organisme : Association Laurette Fugain
Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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